Muscarinic M1 and M3 Receptors,IP3 and cGMP Functional Regulation in Streptozotocin Induced Diabetic Rats: Insulin and Somatotropin Induced Rejuvenation as a Function of Age

Muscarinic M1 and M3 Receptors,IP3 and cGMP Functional Regulation in Streptozotocin Induced Diabetic Rats: Insulin and Somatotropin Induced Rejuvenation as a Function of Age

Author:

Savitha, Balakrishnan; Dr. Paulose, C S

Abstract:

The present study describes that acetylcholine through muscarinic Ml and
M3 receptors play an important role in the brain function during diabetes as a function
of age. Cholinergic activity as indicated by acetylcholine esterase, a marker for
cholinergic function, decreased in the brain regions - the cerebral cortex, brainstem
and corpus striatum of old rats compared to young rats. in diabetic condition, it was
increased in both young and old rats in cerebral cortex, and corpus striatum while in
brainstem it was decreased. The functional changes in the muscarinic receptors were
studied in the brain regions and it showed that muscarinic M I receptors of old rats
were down regulated in cerebral cortex while in corpus striatum and brainstem it was
up regulated. Muscarinic M3 receptors of old rats showed no significant change in
cerebral cortex while in corpus striatum and brainstem muscarinic receptors were
down regulated. During diabetes, muscarinic M I receptors were down regulated in
cerebral cortex and brainstem of young rats while in corpus striatum they were up
regulated. In old rats, M I receptors were up regulated in cerebral cortex, corpus
striatum and in brainstem they were down regulated. Muscarinic M3 receptors were
up regulated in cerebral cortex and brainstem of young rats while in corpus striatum
they were down regulated. In old rats, muscarinic M l receptors were up regulated in
cerebral cortex, corpus striatum and brainstem. In insulin treated diabetic rats the
activity of the receptors were reversed to near control. Pancreatic muscarinic M3
receptor activity increased in the pancreas of both young and old rats during diabetes.
In vitro studies using carbachol and antagonists for muscarinic Ml and M3 receptor
subtypes confirmed the specific receptor mediated neurotransmitter changes during
diabetes. Calcium imaging studies revealed muscarinic M I mediated Ca2
+ release
from the pancreatic islet cells of young and old rats. Electrophysiological studies
using EEG recording in young and old rats showed a brain activity difference during diabetes. Long term low dose STH and INS treated rat brain tissues were used for
gene expression of muscarinic Ml, M3, glutamate NMDARl, mGlu-5,alpha2A, beta2,
GABAAa1 and GABAB, DAD2 and 5-HT 2C receptors to observe the neurotransmitter
receptor functional interrelationship for integrating memory, cognition and
rejuvenating brain functions in young and old. Studies on neurotransmitter receptor
interaction pathways and gene expression regulation by second messengers like IP3
and cGMP in turn will lead to the development of therapeutic agents to manage
diabetes and brain activity.From this study it is suggested that functional improvement of
muscarinic Ml, M3, glutamate NMDAR1, mGlu-5, alpha2A, beta2, GABAAa1 and GABAB,
DAD2 and 5-HT 2C receptors mediated through IP3 and cGMP will lead to therapeutic
applications in the management of diabetes. Also, our results from long term low dose
STH and INS treatment showed rejuvenation of the brain function which has clinical
significance in maintaining healthy period of life as a function of age.

Description:

Department of Biotechnology,
Cochin University of Science and Technology